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Suppression of induced pluripotent stem cell generation by the p53-p21 pathway

Hyenjong Hong1, Kazutoshi Takahashi, Tomoko Ichisaka

  • 1Center for iPS Cell Research and Application (CiRA), Institute for Integrated Cell-Material Sciences, Kyoto University, Kyoto 606-8507, Japan.

Nature
|August 12, 2009
PubMed

Insights

Suppressing p53 (tumor suppressor) significantly enhances induced pluripotent stem (iPS) cell generation from various cell types. This finding reveals p53

Area of Science:

  • Stem cell biology
  • Cancer biology
  • Molecular genetics

Background:

  • Induced pluripotent stem (iPS) cell generation from somatic cells typically requires specific transcription factors (Oct3/4, Sox2, Klf4, c-Myc).
  • The efficiency of reprogramming somatic cells into iPS cells remains a significant challenge.
  • The role of p53 in regulating iPS cell generation efficiency is not fully understood.

Purpose of the Study:

  • To investigate the effect of p53 suppression on the efficiency of iPS cell generation.
  • To elucidate the underlying mechanisms by which p53 influences reprogramming.
  • To identify p53-regulated genes involved in the pluripotency induction process.

Main Methods:

  • Generation of p53-deficient mouse embryonic fibroblasts.
  • Reprogramming of mouse and human somatic cells using defined factors with and without p53 suppression.
  • Analysis of iPS cell generation efficiency and characteristics.
  • DNA microarray analysis to identify p53-regulated genes.
  • Functional analysis of identified genes.

Main Results:

  • Deletion of p53 (tumor suppressor) dramatically increased iPS cell generation efficiency in mouse fibroblasts, reaching up to 10% without c-Myc.
  • p53 deficiency facilitated the generation of integration-free iPS cells via plasmid transfection and enabled reprogramming of terminally differentiated T lymphocytes.
  • Suppression of p53 also enhanced human iPS cell generation efficiency.
  • DNA microarray identified 34 common p53-regulated genes in mouse and human fibroblasts, implicating the p53-p21 pathway.

Conclusions:

  • The p53-p21 pathway acts as a critical barrier to efficient iPS cell generation, in addition to its known role in preventing tumorigenesis.
  • Targeting the p53 pathway offers a promising strategy to improve the efficiency and applicability of iPS cell technology.
  • Understanding p53's role provides insights into both stem cell reprogramming and cancer biology.

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